This proposal entitled "Clinical Studies of Non-Hodgkins Lymphomas" is the first component of an Interactive Project Research Grant entitled "Clinical Cytogenetic and Molecular Studies of Lymphoma" (project coordinator: James P. O'Brien, M.D.). The other components of this program are "Cytogenetic Analysis of Tumor Progression in Lymphoma" K. Offit, M.D., M.P.H., P.I., "Molecular Diagnosis and Pathogenesis of Lymphoma" A. Zelenetz, M.D., Ph.D., P.I. Two clinical protocols are proposed within this application and will provide the opportunity (1) to investigate novel treatment approaches to intermediate and low grade lymphomas, (2) to acquire tumor tissue for basic biologic studies, and (3) to provide a framework for interpretation of results of the associated cytogenetic and molecular studies within a uniform patient population receiving defined treatment programs. The first clinical trial will determine the feasibility and assess the efficacy of the NHL- 15M Protocol, a novel treatment program for previously untreated patients with intermediate grade non-Hodgkin's lymphoma studying the addition of R-Verapamil (R-V) (a multidrug resistance reversal agent) to the dose intense doxorubin/vincristine induction phase of the NHL-15 Protocol (Blood 8, 157a 1992). The effect of R-V on doxorubicin pharmacokinetics will be studied to assess the effect of this drug on doxorubicin metabolism and elimination. Cerebral spinal fluid levels of doxorubicin will be measured with and without R-V to examine the effect of this MDR reversal agent on blood brain barrier function. The second proposed clinical protocol will be a phase III prospective randomized comparison of CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) vs. CHOP followed by high dose cyclophosphamide/G-CSF intensification, for patients with advanced stage low grade lymphomas. Tissue specimens including tumor, blood, and bone marrow will be obtained from patients at specified times on these treatments for studies to be performed in the associated components of this IPRG listed above.